Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation

doi:10.1016/S0091-6749(98)70018-1

Journal of Allergy and Clinical Immunology

Volume 102, Issue 5, November 1998, Pages 783-788

https://doi.org/10.1016/S0091-6749(98)70018-1 Get rights and content

Abstract

Background: Bronchial asthma is characterized by airway structural changes, including mucosal inflammation and subepithelial collagen deposition. An imbalance between the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is thought to play a critical role in the synthesis or degradation of the extracellular matrix of the airway architecture. However, the relationship between subepithelial basement membrane thickness and these enzymes in asthma has not been determined. Objective: We compared the thickness of collagen and tenascin deposition and the expression of MMP-9 and TIMP-1 in bronchial biopsy specimens from subjects with asthma and control subjects. Methods: Bronchial biopsy specimens were obtained from 25 subjects with asthma and 10 healthy control subjects to estimate the extent of collagen and tenascin deposition in subepithelial reticular basement membrane by immunohistochemical staining. Using a computer-assisted image analysis system, we quantitated expression of both epithelial and submucosal MMP-9 and TIMP-1. The numbers of inflammatory cells were also determined. Results: Subjects with asthma exhibited greater thickness of collagen III (P < .01), collagen V (P < .01), and tenascin (P < .01) deposition in reticular basement membrane than did control subjects. The proportions of epithelium and submucosa immunoreactive to MMP-9 and TIMP-1 were significantly higher in the subjects with asthma than in the control subjects (each P < .001). Submucosal expression of MMP-9 was significantly higher than that of TIMP-1 in subjects with asthma (P < .01). Significant correlations were found between the number of myofibroblasts and thicknesses of collagen III (r_s = 0.70, P < .001), collagen V (r_s = 0.67, P < .001), and tenascin (r_s = 0.58, P < .01) in subjects with asthma. On the other hand, the number of eosinophils was correlated with degree of mucosal expression of MMP-9 (r_s = 0.43, P < .05) and TIMP-1 (r_s = 0.69, P < .001). In subjects with asthma, a significant inverse correlation was found between subepithelial fibrosis and FEV₁ (type III collagen, r_s = –0.89, P < .001; type V collagen, r_s = –0.90, P < .001; tenascin, r_s = –0.88, P < .001), and airway responsiveness (type III collagen, r_s = –0.59, P < .01; type V collagen, r_s = –0.47, P < .05; tenascin, r_s = –0.48, P < .05). Conclusion: These findings suggest that collagen III, collagen V, and tenascin deposition in basement membrane in subjects with bronchial asthma are associated with increased expression of MMP-9, which may be produced by eosinophils, and that airway remodeling in subjects with asthma may be related to air-flow obstruction and airway hyperresponsiveness. (J Allergy Clin Immunol 1998;102:783-8.)

Section snippets

Subjects

Twenty-five nonsmoking subjects with asthma were recruited from our hospital. Asthma was diagnosed according to the criteria of the American Thoracic Society.¹⁶ The duration of asthma ranged from 1 to 34 years. Of these 25 patients, 6 were nonatopic as determined by clinical history and a skin prick test performed with common aeroallergens generally used on the skin. No patients had received inhaled or oral corticosteroids or any other anti-inflammatory drugs such as sodium cromoglycate or

Thickness of the RBM

The thickness of the RBM measured with immunohistochemical staining for collagen type III, type V, and tenascin was significantly larger in patients with asthma than in control subjects, but the thickness of the RBM measured with staining for collagen type IV was not (Table II).

. Thickness of subtypes of collagen and tenascin deposition in the subepithelial basement membrane

Empty Cell	Bronchial asthma	Control
Collagen III (μm)	10.3* (5.3-15.2)	4.5 (3.7-5.7)
Collagen IV (μm)	5.3 (4.4-6.0)	5.0 (4.4-5.7)
Collagen V

DISCUSSION

The present study showed that, by comparison with control subjects: (1) the thicknesses of collagen type III, V, and tenascin deposition were significantly increased in the bronchial RBM in patients with asthma; (2) MMP-9 and TIMP-1 immunoreactivities were significantly increased in both the epithelium and submucosa of patients with asthma; and (3) submucosal expression of MMP-9 was stronger than that of TIMP-1 in patients with asthma. Moreover, in the bronchial biopsy specimens obtained from

Acknowledgements

The authors thank all the subjects who volunteered to participate in this study.

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^☆: From the Second Department of Internal Medicine, Toho University School of Medicine, Tokyo.

^☆☆: Supported in part by a grant from Takeda Chemical Industries Ltd, Osaka, Japan.

^★: Reprint requests: Makoto Hoshino, MD, Second Department of Internal Medicine, Toho University School of Medicine 6-11-1, Omori-nishi, Ota-ku, Tokyo, Japan.

^★★: 0091-6749/98 $5.00 + 0 1/1/93514

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Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation☆,☆☆,★,★★

Abstract

Section snippets

Subjects

Thickness of the RBM

DISCUSSION

Acknowledgements

J Allergy Clin Immunol

Lancet

Curr Opin Cell Biol

Biochem Biophys Acta

Chest

Collagen Rel Res

Chest

Damage of the airway epithelium and bronchial reactivity in patients with asthma

Am Rev Respir Dis

Eosinophilic inflammation in asthma

N Engl J Med

Morphology of the basement membrane

Microsc Res Techniq